DESCRIPTION

Mirena (levonorgestrel-releasing intrauterine system)
contains 52 mg of LNG, a progestin, and is intended to provide an initial
release rate of approximately 20 mcg/day of LNG.

Levonorgestrel USP,
(-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active
ingredient in Mirena, has a molecular weight of 312.4, a molecular formula of C21H28O2,
and the following structural formula:

Mirena

Mirena consists of a T-shaped
polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core)
around the vertical stem. The reservoir consists of a white or almost white
cylinder, made of a mixture of levonorgestrel and silicone
(polydimethylsiloxane), containing a total of 52 mg levonorgestrel. The
reservoir is covered by a semi-opaque silicone (polydimethylsiloxane) membrane.
The T-body is 32 mm in both the horizontal and vertical directions. The
polyethylene of the T-body is compounded with barium sulfate, which makes it
radiopaque. A monofilament brown polyethylene removal thread is attached to a
loop at the end of the vertical stem of the T-body. The polyethylene of the
removal thread contains iron oxide as a colorant (see Figure 10).

The components of Mirena,
including its packaging, are not manufactured using natural rubber latex.

Figure 10: Mirena

Inserter

Mirena is packaged sterile
within an inserter. The inserter (Figure 11), which is used for insertion of
Mirena into the uterine cavity, consists of a symmetric two-sided body and
slider that are integrated with flange, lock, pre-bent insertion tube and
plunger. The outer diameter of the insertion tube is 4.4 mm. The vertical stem
of Mirena is loaded in the insertion tube at the tip of the inserter. The arms
are pre-aligned in the horizontal position. The removal threads are contained
within the insertion tube and handle. Once Mirena has been placed, the inserter
is discarded.

Figure 11: Diagram of Inserter

For Consumers

What are the possible side effects of levonorgestrel intrauterine system (Mirena)?

Get emergency medical help if you have severe pain in your lower stomach or side. This could be a sign of a tubal pregnancy (a pregnancy that implants in the fallopian tube instead of the uterus). A tubal pregnancy is a medical emergency.

The levonorgestrel intrauterine device may become embedded into the wall of the uterus, or may perforate (form a hole) in the uterus. If this occurs, the device may no longer prevent pregnancy, or it may move outside the uterus and cause scarring, infection, or damage to other organs. If the device embeds in or...

INDICATIONS

Mirena is also indicated for the treatment of heavy
menstrual bleeding in women who choose to use intrauterine contraception as
their method of contraception.

Mirena is recommended for women
who have had at least one child.

The system should be replaced
after 5 years if continued use is desired.

DOSAGE AND ADMINISTRATION

Mirena contains 52 mg of levonorgestrel (LNG). Initially,
LNG is released at a rate of approximately 20 mcg/day. This rate decreases
progressively to half that value after 5 years.

Mirena must be removed by the end of the fifth year and
can be replaced at the time of removal with a new Mirena if continued
contraceptive protection is desired.

Mirena is supplied within an inserter in a sterile
package (see Figure 1) that must not be opened until required for insertion [see
DESCRIPTION]. Do not use if the seal of the sterile package is broken or
appears compromised. Use strict aseptic techniques throughout the insertion
procedure [see WARNINGS AND PRECAUTIONS].

Insertion Instructions

A complete medical and social history should be obtained
to determine conditions that might influence the selection of a
levonorgestrel-releasing intrauterine system (LNG IUS) for contraception. If
indicated, perform a physical examination, and appropriate tests for any forms
of genital or other sexually transmitted infections. [See CONTRAINDICATIONS
and WARNINGS AND PRECAUTIONS]

Follow the insertion instructions Exactly as described in
order to ensure proper placement and avoid premature release of Mirena from the
inserter. Once released, Mirena cannot be re-loaded.

Mirena should be inserted by a trained healthcare
provider. Healthcare providers should become thoroughly familiar with the
insertion instructions before attempting insertion of Mirena.

Insertion may be associated with some pain and/or
bleeding or vasovagal reactions (for example, syncope, bradycardia), or with
seizure in an epileptic patient, especially in patients with a predisposition
to these symptoms. Consider administering analgesics prior to insertion.

Timing Of Insertion

Insert Mirena into the uterine cavity during the first
seven days of the menstrual cycle or immediately after a first trimester
abortion. Back up contraception is not needed when Mirena is inserted as
directed.

Postpone postpartum insertion and insertions following
second trimester abortions a minimum of six weeks or until the uterus is fully
involuted. If involution is delayed, wait until involution is complete before
insertion [see WARNINGS AND PRECAUTIONS].

Thoroughly cleanse the cervix and vagina with a suitable
antiseptic solution.

Prepare to sound the uterine cavity. Grasp the upper lip
of the cervix with a tenaculum forceps and gently apply traction to stabilize
and align the cervical canal with the uterine cavity. Perform a paracervical
block if needed. If the uterus is retroverted, it may be more appropriate to
grasp the lower lip of the cervix. The tenaculum should remain in position and
gentle traction on the cervix should be maintained throughout the insertion
procedure.

Gently insert a uterine sound to check the patency of the
cervix, measure the depth of the uterine cavity in centimeters, confirm cavity
direction, and detect the presence of any uterine anomaly. If you encounter
difficulty or cervical stenosis, use dilatation, and not force, to overcome
resistance. If cervical dilatation is required, consider using a paracervical
block.

The uterus should sound to a depth of 6 to 10 cm.
Insertion of Mirena into a uterine cavity less than 6 cm by sounding may
increase the incidence of expulsion, bleeding, pain, perforation, and possibly
pregnancy.

Insertion Procedure

Proceed with insertion only after completing the above
steps and ascertaining that the patient is appropriate for Mirena. Ensure use
of aseptic technique throughout the entire procedure.

Step 1-Opening of the Package

Open the package (Figure 1). The contents of the
package are sterile.

Figure 1: Opening the Mirena Package

Using sterile gloves lift the handle of the sterile
inserter and remove from the sterile package.

Step 2-Load Mirena Into the Insertion Tube

Push the slider forward as far as possible in the
direction of the arrow thereby moving the insertion tube over the Mirena T-body
to load Mirena into the insertion tube (Figure 2). The tips of the arms will
meet to form a rounded end that extends slightly beyond the insertion tube.

Figure 2: Move slider all
the way to the forward position to load Mirena

Maintain forward pressure with
your thumb or forefinger on the slider. DO NOT move the slider downward at this
time as this may prematurely release the threads of Mirena. Once the slider is
moved below the mark, Mirena cannot be re-loaded.

Step 3-Setting the Flange

Holding the slider in this
forward position, set the upper edge of the flange to correspond to the uterine
depth (in centimeters) measured during sounding (Figure 3).

Figure 3: Setting the flange

Step 4-Mirena Is Now Ready To Be Inserted

Continue holding the slider in this forward position.
Advance the inserter through the cervix until the flange is approximately 1.5-2
cm from the cervix and then pause (Figure 4).

Figure 4: Advancing insertion tube until flange is 1.5
to 2 cm from the cervix

Step 5-Open the Arms

While holding the inserter steady, move the slider down
to the mark to release the arms of Mirena (Figure 5). Wait 10 seconds for the
horizontal arms to open completely.

Figure 5: Move the slider back to the mark to release
and open the arms

Step 6-Advance to Fundal
Position

Advance the inserter gently
towards the fundus of the uterus until the flange touches the cervix. If you
encounter fundal resistance do not continue to advance. Mirena is now in the
fundal position (Figure 6). Fundal positioning of Mirena is important to
prevent expulsion.

Figure 6: Move Mirena into the fundal position

Step 7-Release Mirena and Withdraw the Inserter

Holding the entire inserter firmly in place, release
Mirena by moving the slider all the way down (Figure 7).

Figure 7. Move the slider all the way down to release
Mirena from the insertion tube

Continue to hold the slider all the way down while you
slowly and gently withdraw the inserter from the uterus.

Using a sharp, curved scissor, cut the threads perpendicular,
leaving about 3 cm visible outside of the cervix [cutting threads at an angle
may leave sharp ends (Figure 8)]. Do not apply tension or pull on the threads
when cutting to prevent displacing Mirena.

Figure 8: Cutting the
threads

Mirena insertion is now
complete. Prescribe analgesics, if indicated. Keep a copy of the Consent Form
with lot number for your records.

Important Information To Consider During Or After Insertion

If you suspect that Mirena is not in the correct
position, check placement (for example, using transvaginal ultrasound). Remove
Mirena if it is not positioned completely within the uterus. A removed Mirena
must not be re-inserted.

If there is clinical concern, exceptional pain or
bleeding during or after insertion, appropriate steps (such as physical
examination and ultrasound) should be taken immediately to exclude perforation.

Patient Follow-up

Reexamine and evaluate patients
4 to 6 weeks after insertion and once a year thereafter, or more frequently if
clinically indicated.

Removal Of Mirena

Timing of Removal

Mirena should not remain in the uterus after 5 years.

If pregnancy is not desired, the removal should be
carried out during menstruation, provided the woman is still experiencing
regular menses. If removal will occur at other times during the cycle, consider
starting a new contraceptive method a week prior to removal. If removal occurs
at other times during the cycle and the woman has had intercourse in the week
prior to removal, she is at risk of pregnancy. [See Continuation of Contraception after Removal]

Tools for Removal

Preparation

Gloves

Speculum

Procedure

Sterile forceps

Removal Procedure

Remove Mirena by applying gentle traction on the threads
with forceps. (Figure 9).

Figure 9: Removal of Mirena

If the threads are not visible, determine location of
Mirena by ultrasound [see WARNINGS AND PRECAUTIONS].

If Mirena is found to be in the uterine cavity on
ultrasound exam, it may be removed using a narrow forceps, such as an alligator
forceps. This may require dilation of the cervical canal. After removal of
Mirena, examine the system to ensure that it is intact.

Removal may be associated with some pain and/or bleeding
or vasovagal reactions (for example, syncope, or a seizure in an epileptic
patient).

Continuation Of Contraception After
Removal

If pregnancy is not desired and if a woman wishes to
continue using Mirena, a new system can be inserted immediately after removal
any time during the cycle.

If a patient with regular cycles wants to start a
different birth control method, time removal and initiation of new method to
ensure continuous contraception. Either remove Mirena during the first 7 days
of the menstrual cycle and start the new method immediately thereafter or start
the new method at least 7 days prior to removing Mirena if removal is to occur
at other times during the cycle.

If a patient with irregular cycles or amenorrhea wants to
start a different birth control method, start the new method at least 7 days
before removal.

HOW SUPPLIED

Dosage Forms And Strengths

Mirena is a LNG-releasing IUS consisting of a T-shaped
polyethylene frame with a steroid reservoir containing a total of 52 mg LNG.

Storage And Handling

Mirena (levonorgestrel-releasing intrauterine system),
containing a total of 52 mg LNG, is available in a carton of one sterile unit NDC# 50419-423-01.

Mirena is supplied sterile. Mirena is sterilized with
ethylene oxide. Do not resterilize. For single use only. Do not use if the
inner package is damaged or open. Insert before the end of the month shown on
the label.

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical studies of
a drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

The data provided reflect the experience with the use of
Mirena in the adequate and well-controlled studies as well as in the supportive
and uncontrolled studies for contraception and heavy menstrual bleeding
(n=5,091). The data cover more than 12,101 women-years of exposure, mainly in
the contraception studies (11,761 women-years). The frequencies of reported
adverse drug reactions represent crude incidences.

Postmarketing Experience

The following adverse reactions
have been identified during post approval use of Mirena. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.

Significant changes (increase or decrease) in
the serum concentrations of the progestin have been noted in some cases of
co-administration with HIV protease inhibitors or with non-nucleoside reverse
transcriptase inhibitors. CYP3A4 inhibitors such as itraconazole or
ketoconazole may increase plasma hormone levels.

Consult the labeling of all concurrently used drugs to
obtain further information about interactions with Mirena or the potential for
enzyme alterations.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Ectopic Pregnancy

Evaluate women for ectopic pregnancy if they become
pregnant with Mirena in place because the likelihood of a pregnancy being
ectopic is increased with Mirena. Up to half of pregnancies that occur with
Mirena in place are likely to be ectopic. Also consider the possibility of
ectopic pregnancy in the case of lower abdominal pain, especially in
association with missed periods or if an amenorrheic woman starts bleeding.

The incidence of ectopic pregnancy in clinical trials
with Mirena, which excluded women with a history of ectopic pregnancy, was
approximately 0.1% per year. The risk of ectopic pregnancy, in women who have a
history of ectopic pregnancy and use Mirena is unknown. Women with a previous
history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher
risk of ectopic pregnancy. Ectopic pregnancy may result in loss of fertility.

Intrauterine Pregnancy

If pregnancy occurs while using Mirena, remove Mirena
because leaving it in place may increase the risk of spontaneous abortion and
preterm labor. Removal of Mirena or probing of the uterus may also result in
spontaneous abortion. In the event of an intrauterine pregnancy with Mirena,
consider the following:

Septic Abortion

In patients becoming pregnant with an IUD in place,
septic abortion -with septicemia, septic shock, and death -may occur.

Continuation Of Pregnancy

If a woman becomes pregnant with Mirena in place and if
Mirena cannot be removed or the woman chooses not to have it removed, warn her
that failure to remove Mirena increases the risk of miscarriage, sepsis,
premature labor and premature delivery. Follow her pregnancy closely and advise
her to report immediately any symptom that suggests complications of the
pregnancy.

Long-term Effects And Congenital Anomalies

When pregnancy continues with Mirena in place, long-term
effects on the offspring are unknown. Congenital anomalies in live births have
occurred infrequently. No clear trend towards specific anomalies has been
observed. Because of the local exposure of the fetus to LNG, the possibility of
teratogenicity following exposure to Mirena cannot be completely excluded. Some
observational data support a small increased risk of masculinization of the
external genitalia of the female fetus following exposure to progestins at
doses greater than those currently used for oral contraception. Whether these
data apply to Mirena is unknown.

Sepsis

Severe infection or sepsis, including Group A
streptococcal sepsis (GAS), have been reported following insertion of Mirena.
In some cases, severe pain occurred within hours of insertion followed by
sepsis within days. Because death from GAS is more likely if treatment is
delayed, it is important to be aware of these rare but serious infections.
Aseptic technique during insertion of Mirena is essential in order to minimize
serious infections such as GAS.

Pelvic Infection

Pelvic Inflammatory Disease (PID)

Mirena is contraindicated in the presence of known or
suspected PID or in women with a history of PID unless there has been a
subsequent intrauterine pregnancy [see CONTRAINDICATIONS]. IUDs have
been associated with an increased risk of PID, most likely due to organisms
being introduced into the uterus during insertion. In clinical trials, total
combined upper genital infections were reported in 3.5% of Mirena users. More
specifically, endometritis was reported in 2.1%, PID in 0.6%, and all other
upper genital infections in ≤ 0.5% of women overall. These infections
occurred more frequently within the first year. In a clinical trial with other
IUDs1 and a clinical trial with an IUD similar to Mirena, the
highest rate occurred within the first month after insertion.

Promptly examine users with complaints of lower abdominal
or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions
or sores. Remove Mirena in cases of recurrent endometritis or PID, or if an
acute pelvic infection is severe or does not respond to treatment.

Women At Increased Risk For PID

PID is often associated with a sexually transmitted
infection, and Mirena does not protect against sexually transmitted infection.
The risk of PID is greater for women who have multiple sexual partners, and
also for women whose sexual partner(s) have multiple sexual partners. Women who
have had PID are at increased risk for a recurrence or re-infection. In
particular, ascertain whether the woman is at increased risk of infection (for
example, leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse).

Asymptomatic PID

Treatment Of PID

Following a diagnosis of PID, or suspected PID,
bacteriologic specimens should be obtained and antibiotic therapy should be
initiated promptly. Removal of Mirena after initiation of antibiotic therapy is
usually appropriate. Guidelines for PID treatment are available from the
Centers for Disease Control (CDC), Atlanta, Georgia.

Actinomycosis

Actinomycosis has been associated with IUDs. Symptomatic
women should have Mirena removed and should receive antibiotics. The
significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD
user is unknown, and so this finding alone does not always require Mirena
removal and treatment. When possible, confirm a Pap smear diagnosis with
cultures.

Irregular Bleeding And Amenorrhea

Mirena can alter the bleeding pattern and result in
spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea.
During the first three to six months of Mirena use, the number of bleeding and
spotting days may be increased and bleeding patterns may be irregular.
Thereafter the number of bleeding and spotting days usually decreases but
bleeding may remain irregular. If bleeding irregularities develop during
prolonged treatment, appropriate diagnostic measures should be taken to rule
out endometrial pathology.

Amenorrhea develops in approximately 20% of Mirena users
by one year. The possibility of pregnancy should be considered if menstruation
does not occur within six weeks of the onset of previous menstruation. Once
pregnancy has been excluded, repeated pregnancy tests are generally not
necessary in amenorrheic women unless indicated, for example, by other signs of
pregnancy or by pelvic pain [see Clinical Studies].

In most women with heavy menstrual bleeding, the number
of bleeding and spotting days may also increase during the initial months of
therapy but usually decrease with continued use; the volume of blood loss per
cycle progressively becomes reduced [see Clinical Studies].

Perforation

Perforation (total or partial, including
penetration/embedment of Mirena in the uterine wall or cervix) may occur most
often during insertion, although the perforation may not be detected until
sometime later. Perforation may reduce contraceptive efficacy and result in
pregnancy. The incidence of perforation during clinical trials, which excluded
breast-feeding women, was < 0.1%.

If perforation occurs, locate and remove Mirena. Surgery
may be required. Delayed detection or removal of Mirena in case of perforation
may result in migration outside the uterine cavity, adhesions, peritonitis,
intestinal perforations, intestinal obstruction, abscesses and erosion of
adjacent viscera.

The risk of perforation may be increased if Mirena is
inserted when the uterus is fixed retroverted or not completely involuted.
Delay Mirena insertion a minimum of six weeks or until involution is complete
following a delivery or a second trimester abortion.

A large postmarketing safety study conducted in Europe
over a 1-year observational period reported that lactation at the time of
insertion of an IUD/IUS was associated with an increased risk of perforation.
For Mirena users, the incidence of uterine perforation was reported as 6.3 per
1,000 insertions for lactating women, compared to 1.0 per 1,000 insertions for
non-lactating women.

Expulsion

Partial or complete expulsion of Mirena may occur
resulting in the loss of contraceptive protection. Expulsion may be associated
with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed.
Mirena typically decreases menstrual bleeding over time; therefore, an increase
of menstrual bleeding may be indicative of an expulsion. The risk of expulsion
may be increased when the uterus is not completely involuted. In clinical
trials, a 4.5% expulsion rate was reported over the 5-year study duration.

Delay Mirena insertion a minimum of six weeks or until
uterine involution is complete following a delivery or a second trimester
abortion. Remove a partially expelled Mirena. If expulsion has occurred, Mirena
may be replaced within 7 days after the onset of a menstrual period, after
pregnancy has been ruled out.

Ovarian Cysts

Because the contraceptive effect of Mirena is mainly due
to its local effects within the uterus, ovulatory cycles with follicular
rupture usually occur in women of fertile age using Mirena. Sometime atresia of
the follicle is delayed and the follicle may continue to grow. Ovarian cysts
have been reported in approximately 8% of women using Mirena. Most of these cysts
are asymptomatic, although some may be accompanied by pelvic pain or
dyspareunia.

In most cases the ovarian cysts disappear spontaneously
during two to three months observation. Evaluate persistent ovarian cysts.
Surgical intervention is not usually required.

Breast Cancer

Women who currently have or have had breast cancer, or
have a suspicion of breast cancer, should not use hormonal contraception
because some breast cancers are hormone-sensitive [see CONTRAINDICATIONS].

Spontaneous reports of breast cancer have been received
during postmarketing experience with Mirena. Observational studies of the risk
of breast cancer with use of a LNG-releasing IUS do not provide conclusive
evidence of increased risk.

Clinical Considerations For Use And Removal

Use Mirena with caution after careful assessment if any
of the following conditions exist, and consider removal of the system if any of
them arise during use:

If the threads are not visible or are significantly
shortened they may have broken or retracted into the cervical canal or uterus.
Consider the possibility that the system may have been displaced (for example,
expelled or perforated the uterus) [see WARNINGS AND PRECAUTIONS]. Exclude
pregnancy and verify the location of Mirena, for example, by sonography, X-ray,
or by gentle exploration of the cervical canal with a suitable instrument. If
Mirena is displaced, remove it. A new Mirena may be inserted at that time or
during the next menses if it is certain that conception has not occurred. If
Mirena is in place with no evidence of perforation, no intervention is
indicated.

Patient Counseling Information

Sexually Transmitted Infections: Counsel the
patient that this product does not protect against HIV infection (AIDS) and
other sexually transmitted infections (STIs).

Risk of Ectopic Pregnancy: Inform the patient
about the risks of ectopic pregnancy, including the loss of fertility. Teach
her to recognize and report to her healthcare provider promptly any symptoms of
ectopic pregnancy. [See WARNINGS AND PRECAUTIONS]

Pregnancy or Suspected Pregnancy: Counsel the
patient to inform her healthcare provider if she determines or suspects she is
pregnant with Mirena in place.

Pelvic Infection: Inform the patient about the
possibility of pelvic inflammatory disease (PID) and that PID can cause tubal
damage leading to ectopic pregnancy or infertility, or infrequently can
necessitate hysterectomy, or cause death. Teach the patient to recognize and
report to her healthcare provider promptly any symptoms of PID. These symptoms
include development of menstrual disorders (prolonged or heavy bleeding),
unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia,
chills, and fever. [See WARNINGS AND PRECAUTIONS]

Irregular Bleeding and Amenorrhea: Counsel the
patient that irregular or prolonged bleeding and spotting, and/or cramps may
occur during the first few weeks after insertion. If her symptoms continue or
are severe she should report them to her healthcare provider. [See WARNINGS
AND PRECAUTIONS]

Perforation and Expulsion: Counsel the patient
that the IUS may be expelled from or perforate the uterus and instruct her on
how she can check that the threads still protrude from the cervix. Caution her
not to pull on the threads and displace Mirena. Inform her that there is no
contraceptive protection if Mirena is displaced or expelled. [See WARNINGS
AND PRECAUTIONS]

Clinical Considerations for Use and Removal: Instruct
the patient to contact her healthcare provider if she experiences any of the following:

Yellowing of the skin or whites of the eyes, as these may
be signs of serious liver problems

Pregnancy or suspected pregnancy

Pelvic pain or pain during sex

HIV positive seroconversion in herself or her partner

Possible exposure to sexually transmitted infections
(STIs)

Unusual vaginal discharge or genital sores

Severe vaginal bleeding or bleeding that lasts a long
time, or if she misses a menstrual period

Inability to feel Mirena's threads

Complete the Follow-up Reminder Card and give to the
patient.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

[See WARNINGS AND PRECAUTIONS]

Use In Specific Populations

Pregnancy

The use of Mirena during an existing or suspected
pregnancy is contraindicated. Many studies have found no harmful effects on
fetal development associated with long-term use of contraceptive doses of oral
progestins. The few studies of infant growth and development that have been
conducted with progestin-only pills have not demonstrated significant adverse
effects. [SeeCONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]

Nursing Mothers

In general, no adverse effects of progestin-only
contraceptives have been found on breastfeeding performance or on the health,
growth, or development of the infant. Isolated postmarketing cases of decreased
milk production have been reported. Small amounts of progestins were observed
to pass into the breast milk of nursing mothers who used Mirena, resulting in
detectable steroid levels in infant serum. [See WARNINGS AND PRECAUTIONS]

Pediatric Use

Safety and efficacy of Mirena have been established in
women of reproductive age. Efficacy is expected to be the same for postpubertal
females under the age of 18 as for users 18 years and older. Use of this
product before menarche is not indicated.

Geriatric Use

Mirena has not been studied in women over age 65 and is
not approved for use in this population.

Hepatic Impairment

No studies were conducted to evaluate the effect of
hepatic disease on the disposition of LNG released from Mirena [seeCONTRAINDICATIONS].

Renal Impairment

No studies were conducted to evaluate the effect of renal
disease on the disposition of LNG released from Mirena.

CLINICAL PHARMACOLOGY

Mechanism Of Action

The local mechanism by which
continuously released LNG enhances contraceptive effectiveness of Mirena has
not been conclusively demonstrated. Studies of Mirena and similar LNG IUS
prototypes have suggested several mechanisms that prevent pregnancy: thickening
of cervical mucus preventing passage of sperm into the uterus, inhibition of
sperm capacitation or survival, and alteration of the endometrium.

Pharmacodynamics

Mirena has mainly local progestogenic effects in the
uterine cavity. The high local levels of LNG2 lead to morphological
changes including stromal pseudodecidualization, glandular atrophy, a
leukocytic infiltration and a decrease in glandular and stromal mitoses.

Ovulation is inhibited in some
women using Mirena. In a 1-year study, approximately 45% of menstrual cycles
were ovulatory, and in another study after 4 years, 75% of cycles were
ovulatory.

Pharmacokinetics

Absorption

Low doses of LNG are
administered into the uterine cavity with the Mirena intrauterine delivery
system. The initial release rate is approximately 20 mcg/day over the first 3
months tested (day 0 to day 90). It is reduced to approximately 18 mcg/day
after 1 year and then decreases progressively to approximately 10 mcg/day after
5 years.

A stable serum concentration,
without peaks and troughs, of LNG of 150-200 pg/mL occurs after the first few
weeks following insertion of Mirena. LNG concentrations after long-term use of
12, 24, and 60 months were 180±66 pg/mL, 192±140 pg/mL, and 159±59 pg/mL,
respectively.

Distribution

The apparent volume of
distribution of LNG is reported to be approximately 1.8 L/kg. It is about 97.5
to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and,
to a lesser extent, serum albumin.

Metabolism

Following absorption, LNG is
conjugated at the 17β-OH position to form sulfate conjugates and, to a
lesser extent, glucuronide conjugates in serum. Significant amounts of
conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also
present in serum, along with much smaller amounts of 3α,
5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. LNG and its
phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic
clearance rates may differ among individuals by several-fold, and this may
account in part for wide individual variations in LNG concentrations seen in
individuals using LNG-containing contraceptive products. In vitro studies have
demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes,
especially CYP3A4.

Excretion

About 45% of LNG and its metabolites are excreted in the
urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
The elimination half-life of LNG after daily oral doses is approximately 17
hours.

Specific Populations

Pediatric: Safety and efficacy of Mirena have been
established in women of reproductive age. Use of this product before menarche is
not indicated.

Geriatric: Mirena has not been studied in women
over age 65 and is not currently approved for use in this population.

Race: No studies have evaluated the effect of race
on pharmacokinetics of Mirena.

Hepatic Impairment: No studies were conducted to
evaluate the effect of hepatic disease on the disposition of Mirena.

Renal Impairment: No formal studies were conducted
to evaluate the effect of renal disease on the disposition of Mirena.

Drug-Drug Interactions

Clinical Studies

Clinical Trials On Contraception

Mirena has been studied for safety and efficacy in two
large clinical trials in Finland and Sweden. In study sites having verifiable
data and informed consent, 1,169 women 18 to 35 years of age at enrollment used
Mirena for up to 5 years, for a total of 45,000 women-months of exposure.
Subjects had previously been pregnant, had no history of ectopic pregnancy, had
no history of pelvic inflammatory disease over the preceding 12 months, were
predominantly Caucasian, and over 70% of the participants had previously used
IUDs (intrauterine devices). The reported 12-month pregnancy rates were less
than or equal to 0.2 per 100 women (0.2%) and the cumulative 5-year pregnancy
rate was approximately 0.7 per 100 women (0.7%).

About 80% of women wishing to become pregnant conceived
within 12 months after removal of Mirena.

Clinical Trial On Heavy Menstrual Bleeding

The efficacy of Mirena in the treatment of heavy
menstrual bleeding was studied in a randomized, open-label, active-control,
parallel-group trial comparing Mirena (n=79) to an approved therapy,
medroxyprogesterone acetate (MPA) (n=81), over 6 cycles. The subjects included
reproductive-aged women in good health, with no contraindications to the drug
products and with confirmed heavy menstrual bleeding ( ≥ 80 mL menstrual
blood loss [MBL]) determined using the alkaline hematin method. Excluded were
women with organic or systemic conditions that may cause heavy uterine bleeding
(except small fibroids, with total volume not > 5 mL). Treatment with Mirena
showed a statistically significantly greater reduction in MBL (see Figure 12)
and a statistically significantly greater number of subjects with successful
treatment (see Figure 13). Successful treatment was defined as proportion of
subjects with (1) end-of-study MBL < 80 mL and (2) a ≥ 50% decrease in
MBL from baseline to end-of-study.

PATIENT INFORMATION

Mirena®
(mur-a-nah)
(levonorgestrel-releasing) Intrauterine System

Mirena does not protect against HIV infection (AIDS)
and other sexually transmitted infections (STIs).

Read this Patient Information carefully before you decide
if Mirena is right for you. This information does not take the place of talking
with your gynecologist or other healthcare provider who specializes in women's
health. If you have any questions about Mirena, ask your healthcare provider.
You should also learn about other birth control methods to choose the one that
is best for you.

What is Mirena?

Mirena is a hormone-releasing system placed in your
uterus by your healthcare provider to prevent pregnancy for up to 5 years.

Mirena can also lessen menstrual blood loss in women who
have heavy menstrual flow and who also want to use a birth control method that
is placed in the uterus to prevent pregnancy.

Mirena can be removed by your healthcare provider at any
time.

Mirena is recommended for women who have had at least one
child.

Mirena is a small flexible plastic T-shaped system that
slowly releases a progestin hormone called levonorgestrel that is often used in
birth control pills. Because Mirena releases levonorgestrel into your uterus,
only small amounts of the hormone enter your blood. Mirena does not contain
estrogen.

Two thin threads are attached to the stem of Mirena. The
threads are the only part of Mirena you can feel when Mirena is in your uterus;
however, unlike a tampon string, the threads do not extend outside your body.

Mirena is small and flexible

What if I need birth control
for more than 5 years?

Mirena must be removed after 5
years. Your healthcare provider can place a new Mirena during the same office
visit if you choose to continue using Mirena.

What if I want to stop using Mirena?

Mirena is intended for long-term use but you can stop
using Mirena at any time by asking your healthcare provider to remove it. You
could become pregnant as soon as Mirena is removed, so you should use another
method of birth control if you do not want to become pregnant.

What if I change my mind about birth control and want
to become pregnant in less than 5 years?

Your healthcare provider can remove Mirena at any time.
You may become pregnant as soon as Mirena is removed. About 8 out of 10 women
who want to become pregnant will become pregnant sometime in the first year
after Mirena is removed.

How does Mirena work?

Mirena may work in several ways including thickening
cervical mucus, inhibiting sperm movement, reducing sperm survival, and
thinning the lining of your uterus. It is not known exactly how these actions
work together to prevent pregnancy.

Mirena can cause your menstrual bleeding to be less by
thinning the lining of the uterus.

How well does Mirena work
for contraception?

The following chart shows the
chance of getting pregnant for women who use different methods of birth
control. Each box on the chart contains a list of birth control methods that
are similar in effectiveness. The most effective methods are at the top of the
chart. The box on the bottom of the chart shows the chance of getting pregnant
for women who do not use birth control and are trying to get pregnant.

Mirena, an intrauterine device
(IUD), is in the box at the top of the chart.

How well does Mirena work
for heavy menstrual bleeding?

In the clinical trial performed
in women with heavy menstrual bleeding and treated with Mirena, almost 9 out of
10 were treated successfully and their blood loss was reduced by more than
half.

Who might use Mirena?

You might choose Mirena if you:

Want long-term birth control
that provides a low chance of getting pregnant (less than 1 in 100)

Want birth control that works
continuously for up to 5 years

Want birth control that is
reversible

Want a birth control method
that you do not need to take daily

Have had at least one child

Want treatment for heavy
periods and are willing to use a birth control method that is placed in the
uterus

Want birth control that does
not contain estrogen

Who should not use Mirena?

Do not use Mirena if you:

Are or might be pregnant;
Mirena cannot be used as an emergency contraceptive

Mirena is placed by your healthcare provider during an
in-office visit.

First, your healthcare provider will examine your pelvis
to find the exact position of your uterus. Your healthcare provider will then
clean your vagina and cervix with an antiseptic solution, and slide a slim
plastic tube containing Mirena into your uterus. Your healthcare provider will
then remove the plastic tube, and leave Mirena in your uterus. Your healthcare
provider will cut the threads to the right length. Placement takes only a few
minutes.

You may experience pain, bleeding or dizziness during and
after placement. If your symptoms do not pass within 30 minutes after
placement, Mirena may not have been placed correctly. Your healthcare provider
will examine you to see if Mirena needs to be removed or replaced.

Should I check that Mirena is in place?

Yes, you should check that Mirena is in proper position
by feeling the removal threads. It is a good habit to do this once a month.
Your healthcare provider should tell you how to check that Mirena is in place.
First, wash your hands with soap and water. You can check by reaching up to the
top of your vagina with clean fingers to feel the removal threads. Do not pull
on the threads. If you feel more than just the threads or if you cannot feel
the threads, Mirena may not be in the right position and may not prevent
pregnancy. Use non-hormonal back-up birth control (such as condoms and
spermicide) and ask your healthcare provider to check that Mirena is still in
the right place.

How soon after placement of Mirena should I return to
my healthcare provider?

Call your healthcare provider if you have any questions
or concerns (see “When should I call my healthcare provider“).
Otherwise, you should return to your healthcare provider for a follow-up visit
4 to 6 weeks after Mirena is placed to make sure that Mirena is in the right
position.

Can I use tampons with Mirena?

Tampons may be used with Mirena.

What if I become pregnant while using Mirena?

Call your healthcare provider right away if you think you
are pregnant. If you get pregnant while using Mirena, you may have an ectopic
pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal
bleeding or abdominal pain may be a sign of ectopic pregnancy.

Ectopic pregnancy is a medical emergency that often
requires surgery. Ectopic pregnancy can cause internal bleeding, infertility,
and even death.

There are also risks if you get pregnant while using
Mirena and the pregnancy is in the uterus. Severe infection, miscarriage,
premature delivery, and even death can occur with pregnancies that continue
with an intrauterine device (IUD). Because of this, your healthcare provider
may try to remove Mirena, even though removing it may cause a miscarriage. If
Mirena cannot be removed, talk with your healthcare provider about the benefits
and risks of continuing the pregnancy.

If you continue your pregnancy, see your healthcare
provider regularly. Call your healthcare provider right away if you get
flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge,
or fluid leaking from your vagina. These may be signs of infection.

It is not known if Mirena can cause long-term effects on
the fetus if it stays in place during a pregnancy.

How will Mirena change my periods?

For the first 3 to 6 months, your period may become
irregular and the number of bleeding days may increase. You may also have frequent
spotting or light bleeding. Some women have heavy bleeding during this time.
After you have used Mirena for a while, the number of bleeding and spotting
days is likely to lessen. There is a small chance that your periods will stop
altogether.

In some women with heavy bleeding, the total blood loss
per cycle progressively decreases with continued use. The number of spotting
and bleeding days may initially increase but then typically decreases in the
months that follow.

Is it safe to breastfeed while using Mirena?

You may use Mirena when you are breastfeeding if more
than six weeks have passed since you had your baby. If you are breastfeeding,
Mirena is not likely to affect the quality or amount of your breast milk or the
health of your nursing baby. However, isolated cases of decreased milk
production have been reported among women using progestin-only birth control
pills. The risk of Mirena becoming attached to (embedded) or going through the
wall of the uterus is increased if Mirena is inserted while you are
breastfeeding.

Will Mirena interfere with sexual intercourse?

You and your partner should not feel Mirena during
intercourse. Mirena is placed in the uterus, not in the vagina. Sometimes your
partner feels the threads. If this occurs, talk with your healthcare provider.

What are the possible side effects of using Mirena?

Mirena can cause serious side effects including:

Pelvic inflammatory disease (PID). Some IUD users
get a serious pelvic infection called pelvic inflammatory disease. PID is usually
sexually transmitted. You have a higher chance of getting PID if you or your
partner have sex with other partners. PID can cause serious problems such as
infertility, ectopic pregnancy or pelvic pain that does not go away. PID is
usually treated with antibiotics. More serious cases of PID may require
surgery. A hysterectomy (removal of the uterus) is sometimes needed. In rare
cases, infections that start as PID can even cause death.

Tell your healthcare provider right away if you have any
of these signs of PID: long-lasting or heavy bleeding, unusual vaginal
discharge, low abdominal (stomach area) pain, painful sex, chills, or fever.

Life-threatening infection. Life-threatening infection can occur within the first few days after Mirena is
placed. Call your healthcare provider immediately if you develop severe pain or
fever shortly after Mirena is placed.

Perforation. Mirena may become attached to
(embedded) or go through the wall of the uterus. This is called perforation. If
this occurs, Mirena may no longer prevent pregnancy. If perforation occurs,
Mirena may move outside the uterus and can cause internal scarring, infection,
or damage to other organs, and you may need surgery to have Mirena removed. The
risk of perforation is increased if Mirena is inserted while you are
breastfeeding.

Common side effects of Mirena include:

Pain, bleeding or dizziness during and after placement.
If these symptoms do not stop 30 minutes after placement, Mirena may not have
been placed correctly. Your healthcare provider will examine you to see if
Mirena needs to be removed or replaced.

Expulsion. Mirena may come out by itself. This is called
expulsion. You may become pregnant if Mirena comes out. If you think that
Mirena has come out, use a backup birth control method like condoms and
spermicide and call your healthcare provider.

Missed menstrual periods. About 2 out of 10 women stop
having periods after 1 year of Mirena use. If you do not have a period for 6
weeks during Mirena use, call your healthcare provider. When Mirena is removed,
your menstrual periods will come back.

Changes in bleeding. You may have bleeding and spotting
between menstrual periods, especially during the first 3 to 6 months. Sometimes
the bleeding is heavier than usual at first. However, the bleeding usually
becomes lighter than usual and may be irregular. Call your healthcare provider
if the bleeding remains heavier than usual or increases after it has been light
for a while.

Cysts on the ovary. About 12 out of 100 women using
Mirena develop a cyst on the ovary. These cysts usually disappear on their own
in a month or two. However, cysts can cause pain and sometimes cysts will need
surgery.

This is not a complete list of possible side effects with
Mirena. For more information, ask your healthcare provider.

Call your doctor for medical advice about side effects.
You may report side effects to the manufacturer at 1-888-842-2937, or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.

After Mirena has been placed, when should I call my
healthcare provider?

Call your healthcare provider if you have any concerns
about Mirena. Be sure to call if you:

Medicines are sometimes prescribed for conditions that
are not mentioned in patient information leaflets. This leaflet summarizes the
most important information about Mirena. If you would like more information,
talk with your healthcare provider. You can ask your healthcare provider for
information about Mirena that is written for health providers.

For more information, go to www.mirena-us.com or call
1-888-842-2937

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.